Meglumine in Combination with Another Therapeutic

ABSTRACT

The invention relates to a method of treating or preventing a condition in a subject, comprising administering to the subject an acceptable composition comprising meglumine or a salt thereof. The invention further relates to a method of improving a physiological function in a subject, comprising administering to the subject an acceptable composition comprising meglumine or a salt thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. patent applicationSer. No. 15/413,455, filed Jan. 24, 2017, which is a division of U.S.patent application Ser. No. 13/962,645, filed Aug. 8, 2013, which claimsthe priority of United States Provisional Patent Application Nos.61/770,553 filed Feb. 28, 2013, and 61/681,241 filed Aug. 9, 2012, allof which applications are hereby incorporated by reference in theirentireties herein.

BACKGROUND OF THE INVENTION

Health is the level of functional or metabolic efficiency of a livingbeing. In humans, health is the general condition of a person's mind,body and spirit, usually meaning to be free from illness, injury or pain(as in “good health,” “good state of health” or “healthy”). According tothe World Health Organization (WHO), health is “a state of completephysical, mental, and social well-being and not merely the absence ofdisease or infirmity” (World Health Organization, Constitution of theWorld Health Organization—Basic Documents, 45^(th) edition, Supplement,October 2006). The maintenance and promotion of health is achievedthrough different combination of physical, mental, and socialwell-being, together sometimes referred to as the “health triangle”(Nutter, 2003, The Health Triangle, Anchor Points, Inc.).

A nutraceutical (a portmanteau of the words “nutrition” and“pharmaceutical”) is a supplement, food or food product that reportedlyprovides health benefits. Such products may range from isolatednutrients, dietary supplements and specific diets to geneticallyengineered foods, herbal products, and processed foods such as cereals,soups, and beverages.

There is a need in the art for novel methods for improving the overallhealth or well-being of a subject. In one aspect, such a method shouldbe effective in treating or preventing conditions that affect thesubject, including effects of aging. In another aspect, such a methodshould be effective in affecting or improving physiological functionsknown to correlate with an overall good state of health or well-being inthe subject. The present invention satisfies this need.

BRIEF SUMMARY OF THE INVENTION

The invention includes a method of ameliorating or preventing weightgain, promoting weight control, or promoting weight loss in a subject inneed thereof. The method comprises administering to the subject aneffective amount of a composition comprising meglumine or a saltthereof; whereby weight gain in the subject is ameliorated or prevented,or weight control or weight loss in the subject is promoted.

The invention also includes a method of treating or preventingdisregulation of blood glucose levels in a subject in need thereof. Themethod comprises administering to a subject an effective amount of acomposition comprising meglumine or a salt thereof; wherebydisregulation of blood glucose levels in the subject is treated orprevented.

The invention further includes a method of treating or preventing muscleweakness or increasing muscle strength in a subject in need thereof. Themethod comprises administering to a subject an effective amount of acomposition comprising meglumine or a salt thereof; whereby muscleweakness in the subject is treated or prevented, or muscle strength inthe subject is increased.

The invention also includes a method of reducing or preventing theincrease of triglyceride levels in a subject in need thereof. The methodcomprises administering to a subject an effective amount of acomposition comprising meglumine or a salt thereof; whereby the increaseof triglyceride levels in the subject is reduced or prevented.

In one embodiment, the subject is further administered medication totreat symptoms of diabetes.

The invention further includes a method of reducing or preventing theincrease of LDL levels in a subject in need thereof. The methodcomprises administering to a subject an effective amount of acomposition comprising meglumine or a salt thereof; whereby the increaseof LDL levels in the subject is reduced or prevented.

In one embodiment, the subject is further administered medication totreat symptoms of diabetes.

The invention also includes a method of reducing or preventing theincrease of total cholesterol levels in a subject in need thereof. Themethod comprises administering to a subject an effective amount of acomposition comprising meglumine or a salt thereof; whereby the increaseof total cholesterol levels in the subject is reduced or prevented.

In one embodiment, the subject is further administered medication totreat symptoms of diabetes.

The invention further includes a method of reducing or preventing theincrease of levels of a lipoprotein particle or apolipoprotein in asubject in need thereof. The method comprises administering to a subjectan effective amount of a composition comprising meglumine or a saltthereof; whereby the increase of levels of the lipoprotein particle orapolipoprotein in the subject is reduced or prevented.

In one embodiment, the lipoprotein particle or apolipoprotein comprisesApo B, LDL-P, sdLDL, Apo A-I or any combinations thereof. In anotherembodiment, the lipoprotein particle or apolipoprotein comprises Apo B,and the Apo B:Apo A-I ratio in the subject is reduced. In yet anotherembodiment, the subject is further administered medication to treatsymptoms of diabetes.

The invention also includes a method of increasing or preventing thereduction of creatine/albumin levels in a subject in need thereof. Themethod comprises administering to a subject an effective amount of acomposition comprising meglumine or a salt thereof, whereby thecreatine/albumin levels in the subject are increased or the reduction ofthe creatine/albumin levels in the subject is prevented.

The invention further includes a method of increasing longevity orpromoting anti-aging effects in a subject in need thereof. The methodcomprises administering to a subject an effective amount of acomposition comprising meglumine or a salt thereof, whereby longevity inthe subject is increased.

The invention also includes a method of improving the skin condition ina subject in need thereof. The method comprises administering to asubject an effective amount of a composition comprising meglumine or asalt thereof; whereby the skin condition in the subject is improved.

The invention further includes a method of improving sexual stamina orperformance in a subject in need thereof. The method comprisesadministering to a subject an effective amount of a compositioncomprising meglumine or a salt thereof; whereby sexual stamina orperformance in the subject is improved.

The invention also includes a method of increasing vitality or energylevels in a subject in need thereof. The method comprises administeringto a subject an effective amount of a composition comprising meglumineor a salt thereof; whereby vitality or energy levels in the subject areincreased.

The invention further includes a method of improving the mentalcapacity, or ameliorating or preventing the onset of dementia, in asubject in need thereof. The method comprises administering to a subjectan effective amount of a composition comprising meglumine or a saltthereof; whereby the mental capacity is improved, or the onset ofdementia in the subject is ameliorated or prevented.

The invention also includes a method of improving or maintaining kidneyfunction in a subject in need thereof. The method comprisesadministering to a subject an effective amount of a compositioncomprising meglumine or a salt thereof; whereby kidney function in thesubject is improved or maintained.

In one embodiment, the composition is administered to the subject by aroute selected from the group consisting of inhalational, oral, rectal,vaginal, parenteral, topical, transdermal, pulmonary, intranasal,buccal, ophthalmic, intrathecal, parenteral, intravenous, and anycombinations thereof. In another embodiment, the composition isadministered to the subject at a frequency selected from the groupconsisting of once a day, twice a day, three times a day, four times aday, once a week, twice a week, three times a week, four times a week,once a month, twice a month, and any combinations thereof. In yetanother embodiment, the composition is administered to the subject at adosage ranging from about 1 ng/kg/application to about 100g/kg/application. In yet another embodiment, the composition isadministered to the subject at a dosage ranging from about 1ng/kg/application to about 100 mg/kg/application. In yet anotherembodiment, the composition is administered to the subject as acontrolled-release formulation. In yet another embodiment, the subjectis a mammal. In yet another embodiment, the mammal is a human.

The invention further includes a composition comprising meglumine or asalt thereof and a first amount of a sweet-tasting compound, wherein thecomposition is suitable for oral consumption by a subject; wherein thesweetness of the composition is equivalent to the sweetness of a secondamount of the sweet-tasting compound, further wherein the composition ishealthier, is less toxic or has fewer undesirable physiological effectsin the subject than the second amount of the sweet-tasting compound.

In one embodiment, the sweet-tasting compound comprises glucose,dextrose, high-fructose corn syrup, mannitol, sorbitol, stevia, xylitol,acesulfame potassium, alitame, aspartame, a salt ofaspartame-acesulfame, cyclamate, dulcin, glucin, neohesperidindihydrochalcone, neotame, saccharin, sucralose, or any combinationsthereof. In another embodiment, the subject is a mammal. In yet anotherembodiment, the mammal is a human.

The invention also includes a composition comprising meglumine or a saltthereof and a therapeutic agent selected from the group consisting ofα-glucosidase inhibitors, lipase inhibitors, sulfonyl ureas,meglitinides, biguanides, thiazolidinediones, pramlintide, incretinmimetics, DPP-IV inhibitors, a salt thereof, and any combinationsthereof. In one embodiment, the therapeutic agent comprises metformin.

BRIEF DESCRIPTION OF THE DRAWINGS

The following detailed description of preferred embodiments of theinvention is better understood when read in conjunction with theappended drawings. For the purpose of illustrating the invention, thereare shown in the drawings embodiments that are presently preferred. Itshould be understood, however, that the invention is not limited to theprecise arrangements and instrumentalities of the embodiments shown inthe drawings.

FIG. 1 is a graph illustrating the average weight of mice treated withvarious doses of meglumine, as a function of time.

FIG. 2 is a graph illustrating the measured 3DG/creatine ratio for micetreated with various doses of meglumine.

FIG. 3 is a graph illustrating the amount of AGE products identified inthe skin of rats treated with meglumine for 32 weeks.

FIG. 4 is a graph illustrating the urinary 3DG levels in rats treatedwith meglumine for 32 weeks.

FIG. 5 is a graph illustrating the urinary isoprostane levels in ratstreated with meglumine for 32 weeks.

FIG. 6 is a graph illustrating the measurement of 3DG imidazolone in theskin of rats treated with meglumine for 32 weeks.

FIG. 7 is a graph illustrating the average fluorescence measured in thekidney tubules and glomeruli of rats treated with meglumine for 32weeks.

FIG. 8 is a graph of an oral glucose tolerance test in mice treated withno meglumine or various doses of meglumine.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to the unexpected discovery thatadministering meglumine (also known as N-methylglucamine, or(2R,3R,4R,5S)-6-methylaminohexane-1,2,3,4,5-pentol) or a salt thereof toa subject results in improvement of the overall state of health of thesubject. In one aspect, administering meglumine to the subjectmitigates, reverses or prevents a physiological condition associatedwith a poor state of health or well-being of the subject (i.e., anunhealthy physiological condition), such as, but not limited to,unwanted weight gain, disregulated blood glucose, muscle weakness, lowenergy level, high triglyceride levels, low creatine/albumin levels, orany combinations thereof. In another aspect, administering meglumine tothe subject improves a physiological function associated with an overallgood state of health or well-being of the subject, such as, but notlimited to, longevity, sexual performance, vitality, energy level,mental capacity, delay of dementia onset, or any combinations thereof.The invention thus contemplates compositions comprising meglumine or asalt thereof to improve the subject's overall state of health asdiscussed herein.

Definitions

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although any methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of the present invention, the preferred methodsand materials are described herein.

As used herein, each of the following terms has the meaning associatedwith it in this section.

The articles “a” and “an” are used herein to refer to one or to morethan one (i.e., to at least one) of the grammatical object of thearticle. By way of example, “an element” means one element or more thanone element.

As used herein when referring to a measurable value such as an amount, atemporal duration, and the like, the term “about” is meant to encompassvariations of ±20% or ±10%, more preferably ±5%, even more preferably±1%, and still more preferably ±0.1% from the specified value, as suchvariations are appropriate to perform the disclosed methods.

As used herein, a “subject” or “individual” or “patient” may be a humanor non-human mammal. Non-human mammals include, for example, livestockand pets, such as ovine, bovine, porcine, canine, feline and murinemammals. Preferably, the subject is human.

As used herein, the term “physiological function” refers to a marker,function, characteristic or parameter, which correlates with the overallstate of health or well-being of a subject. The physiological functionmay be measured objectively or subjectively.

As used herein, the term “physiological condition” refers to acondition, diagnosis or parameter determined in or characteristic of asubject. The physiological condition may be measured objectively orsubjectively.

As used herein, the term “anti-aging effects” as associated with acompound refers to the capacity of the compound to eliminate or minimizethe effects of aging in a subject, such as loss of energy and stamina,and development of age-related conditions. “Anti-aging effects” alsorefers to the ability of a compound to extend the life of the subjectover the applicable life expectancy.

As used herein, “an unhealthy condition” refers to a state of health ofan animal wherein the animal cannot maintain homeostasis, and wherein ifthe condition is not ameliorated then the animal's health continues todeteriorate.

As used herein, “an unhealthy condition” in an animal also refers to astate of health in which the animal is able to maintain homeostasis, butin which the animal's state of health is less favorable than it would bein the absence of the condition. Left untreated, a condition does notnecessarily cause a further decrease in the animal's state of health.

As used herein, a “normal” subject with respect to the condition doesnot present the characteristic, symptoms or effects of the condition.

As used herein, a “normal” subject with respect to the physiologicalfunction presents a physiological function that correlates with ahealthy status.

As used herein, the term “binding” refers to the adherence of moleculesto one another, such as, but not limited to, enzymes to substrates,ligands to receptors, antibodies to antigens, DNA binding domains ofproteins to DNA, and DNA or RNA strands to complementary strands.

As used herein, the term “biological sample” refers to samples obtainedfrom a subject, including skin, hair, tissue, blood, plasma, cells,sweat and urine.

As used herein, a “compound” refers to one or more chemical entities,each of which may independently be isolated from nature or synthesized.

As used herein, an “instructional material” includes a publication, arecording, a diagram, a video, or any other medium of expression thatmay be used to communicate the usefulness of the compositions usefulwithin the invention in the kit for preventing or treating the variousconditions recited herein, or improving the physiological functionsrecited herein. Optionally or alternately, the instructional materialmay describe one or more methods of alleviating or treating theconditions or improving the physiological functions in a cell or atissue of a mammal. The instructional material of the kit of theinvention may, for example, be affixed to a container that contains acomposition useful within the invention or be shipped together with acontainer that contains a composition useful within the invention.Alternatively, the instructional material may be shipped separately fromthe container with the intention that the instructional material and acomposition useful within the invention be used cooperatively by therecipient.

As used herein, the term “skin” refers to the commonly used definitionof skin, e.g., the epidermis and dermis, and the cells, glands, andconnective tissue which comprise the skin.

As used herein, the term “treatment” or “treating” is defined as theapplication or administration of a composition useful within theinvention (alone or in combination with another agent), to a subject, orapplication or administration of a composition useful within theinvention to an isolated tissue or cell line from a subject (forexample, for diagnosis or ex vivo applications), who has an unhealthyphysiological condition contemplated herein, a symptom of or thepotential to develop an unhealthy physiological condition contemplatedherein, with the purpose to prevent, cure, heal, alleviate, relieve,alter, remedy, ameliorate, improve or affect an unhealthy physiologicalcondition contemplated herein, the symptoms of or the potential todevelop an unhealthy physiological condition contemplated herein.Similar considerations apply to improving the physiological functions orparameters contemplated within the invention. Such treatments may bespecifically tailored or modified, based on knowledge obtained from thefield of pharmacogenomics.

As used herein, “alleviating a condition,” means reducing the severityof the symptom of the condition.

As used herein, a “prophylactic” treatment is a treatment administeredto a subject who does not exhibit signs of a condition or exhibits onlyearly signs of the condition for the purpose of decreasing the risk ofdeveloping pathology associated with the condition.

As used herein, the term “prevent” or “prevention” means no conditiondevelopment if none had occurred, or no further condition development ifthere had already been development of the condition. Also considered isthe ability of one to prevent some or all of the symptoms associatedwith the condition.

As used herein, the term “treat” means reducing the frequency with whichsymptoms are or may be experienced by a patient or subject oradministering a compound to reduce the severity with which symptoms areor may be experienced. An appropriate amount of the compound in anyindividual case may be determined by one of ordinary skill in the artusing routine experimentation.

As used herein, the term “effective amount” of a compound or compositionrefers to the amount of the compound or composition that is sufficientto provide a beneficial effect to the subject to which the compound orcomposition is administered.

As used herein, the term “acceptable” refers to a material, such as acarrier or diluent, which does not abrogate the biological activity orproperties of the compound or composition, and is relatively non-toxic,i.e., the material may be administered to an individual without causingundesirable biological effects or interacting in a deleterious mannerwith any of the components of the composition in which it is contained.

As used herein, the language “acceptable salt” refers to a salt of theadministered compounds prepared from acceptable non-toxic acids,including inorganic acids, organic acids, solvates, hydrates, orclathrates thereof.

As used herein, the term “composition” refers to a mixture of at leastone compound useful within the invention with other chemical components,such as carriers, stabilizers, diluents, dispersing agents, suspendingagents, thickening agents, and/or excipients. The compositionfacilitates administration of the compound to an organism. Multipletechniques of administering a compound exist in the art including, butnot limited to: intravenous, oral, aerosol, parenteral, ophthalmic,pulmonary and topical administration. In one embodiment, the compositionis non-toxic.

The language “acceptable carrier” includes an acceptable salt,acceptable material, composition or carrier, such as a liquid or solidfiller, diluent, excipient, solvent or encapsulating material, involvedin carrying or transporting a compound(s) of the present inventionwithin or to the subject such that it may perform its intended function.The acceptable carrier is preferably non-toxic. Typically, suchcompounds are carried or transported from one organ, or portion of thebody, to another organ, or portion of the body. Each salt or carriermust be “acceptable” in the sense of being compatible with the otheringredients of the formulation, and not injurious to the subject. Someexamples of materials that may serve as acceptable carriers include:sugars, such as lactose, glucose and sucrose; starches, such as cornstarch and potato starch; cellulose, and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose and cellulose acetate; powderedtragacanth; malt; gelatin; talc; excipients, such as cocoa butter andsuppository waxes; oils, such as peanut oil, cottonseed oil, saffloweroil, sesame oil, olive oil, corn oil and soybean oil; glycols, such aspropylene glycol; polyols, such as glycerin, sorbitol, mannitol andpolyethylene glycol; esters, such as ethyl oleate and ethyl laurate;agar; buffering agents, such as magnesium hydroxide and aluminumhydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer'ssolution; ethyl alcohol; phosphate buffer solutions; diluent;granulating agent; lubricant; binder; disintegrating agent; wettingagent; emulsifier; coloring agent; release agent; coating agent;sweetening agent; flavoring agent; perfuming agent; preservative;antioxidant; plasticizer; gelling agent; thickener; hardener; settingagent; suspending agent; surfactant; humectant; carrier; stabilizer; andother non-toxic compatible substances employed in non-toxicformulations, or any combination thereof. As used herein, “acceptablecarrier” also includes any and all coatings, antibacterial andantifungal agents, and absorption delaying agents, and the like that arecompatible with the activity of the compound, and are physiologicallyacceptable to the subject. Supplementary active compounds may also beincorporated into the compositions.

The term “standard,” as used herein, refers to something used forcomparison. For example, it can be a known standard agent or compoundadministered and used for comparing results when administering a testcompound, or it can be a standard parameter or function measured toobtain a control value when measuring an effect of an agent or compoundon a parameter or function. Standard can also refer to an “internalstandard”, such as an agent or compound which is added at known amountsto a sample and is useful in determining such things as purification orrecovery rates when a sample is processed or subjected to purificationor extraction procedures before a marker of interest is measured.Internal standards are often a purified marker of interest which hasbeen labeled, such as with a radioactive isotope, allowing it to bedistinguished from an endogenous marker.

Compositions

The invention includes a composition comprising meglumine or a saltthereof and a first amount of a sweet-tasting compound, wherein thecomposition is suitable for oral consumption by a subject; wherein thesweetness of the composition is equivalent to the sweetness of a secondamount of the sweet-tasting compound, further wherein the composition ishealthier, is less toxic or has fewer undesirable physiological effectsin the subject than the second amount of the sweet-tasting compound.

In one embodiment, the sweet-tasting compound comprises glucose,dextrose, high-fructose corn syrup, mannitol, sorbitol, stevia, xylitol,acesulfame potassium, alitame, aspartame, a salt ofaspartame-acesulfame, cyclamate, dulcin, glucin, neohesperidindihydrochalcone, neotame, saccharin, sucralose, or any combinationsthereof. In another embodiment, the subject is a mammal. In yet anotherembodiment, the mammal is a human.

The invention includes a composition comprising meglumine or a saltthereof and a therapeutic agent selected from the group consisting ofα-glucosidase inhibitors, lipase inhibitors, sulfonyl ureas,meglitinides, biguanides, thiazolidinediones, pramlintide, incretinmimetics, DPP-IV inhibitors, HSGLT2 inhibitor, a salt thereof, and anycombinations thereof. In one embodiment, the therapeutic agent comprisesmetformin.

In one aspect, a composition comprising meglumine or a salt thereof anda therapeutic agent is contemplated within the invention. Suchcomposition is useful in mitigating, reversing or preventing aphysiological condition associated with a poor state of health orwell-being of the subject (i.e., an unhealthy physiological condition),such as, but not limited to, unwanted weight gain, disregulated bloodglucose, high triglyceride levels, low creatine/albumin levels, or anycombinations thereof. In one embodiment, the therapeutic agent is usedto treat symptoms of diabetes in a subject in need thereof. In anotherembodiment, the diabetes is type 2 diabetes.

Non-limiting examples of therapeutic agents contemplated within theinvention are:

α-glucosidase inhibitors: inhibit upper GI enzymes (α-glucosidases)responsible for digesting carbohydrates, slowing absorption of glucose;also cause slower rise in postprandial blood glucose concentrations.Non-limiting examples: acarbose (Precose, Glucobay); miglitol (Glyset);voglibose (Vogseal, Volix, Basen).

lipase inhibitors: inhibit pancreatic and gastric lipases, blocking fatabsorption. Non-limiting examples: orlistat (Xenical, Alli).

sulfonyl ureas: act as insulin secretagogues, triggering insulin releaseby interacting with the ATP-dependent potassium channel of thepancreatic β-cells. The net result is that more insulin is released atall blood glucose concentrations. They are the most commonly used drugsfor treatment of patients with type 2 diabetes, but, since they triggerrelease of insulin itself, the combination of insulin & sulfonyl ureasis not common. Non-limiting examples: 1^(st) generation of sulfonylureas—acetohexamide, chlorpropamide (Diabinese), tolbutamide (Orinase),tolazamide; 2^(nd) generation of sulfonyl ureas—gliclazide (Diamicron R,Diamicron MR), glyburide or glibenclamide (Diabeta, Micronase, Glynase),glipizide (Glucotrol, Glucotrol XL), glimepiride (Amaryl), gliquidone(Glurenorm).

meglitinides: short-acting glucose-lowering drugs, acting by regulatingATP-dependent potassium channels in pancreatic β-cells like sulfonylureas; structurally different from sulfonylureas and act via differentreceptors as well. Non-limiting examples: mitiglinide (Glufast);nateglinide (Starlix); repaglinide (Prandix).

biguanides: reduce glucose release from the liver and increase glucoseuptake by skeletal muscle. Metformin is the preferred initial treatmentof type 2 diabetes, with good glycemic efficacy, absence of weight gainand hypoglycemia, general tolerability and low cost. The combination ofmetformin & insulin is generally associated with lower weight gain thaninsulin by itself or the combination of insulin & sulfonylureas. Thetriple combination of a sulfonyl urea, metformin and insulin glarginehas been shown to have fewer adverse effects, fewer lipid profileproblems and lower cost than the triple combination of a sulfonyl urea,metformin and rosiglitazone. Non-limiting examples: metformin(Glucophage); phenformin (DBI); buformin (Glybigid, Glybigidum).

thiazolidinediones: increase insulin sensitivity by acting on adipose,muscle and liver tissue to increase glucose utilization and decreaseglucose production. The mechanism of action is not fully understood, butthey seem to bind and activate one or more peroxisomeproliferator-activated receptors (PPARs), regulating gene expression.Non-limiting examples: rosiglitazone (Avandia); pioglitazone (Actos);troglitazone (Rezulin); tesaglitazar (Pargluva).

pramlintide (Symlin)—also known as islet amyloid polypeptide, is asynthetic analog of human amylin that slows gastric emptying andsuppresses glucagon, reducing postprandial rises in blood glucoselevels; approved by the FDA to lower blood sugar in type 1 diabetespatients.

incretin mimetics: these insulin secretagogues act as glucagon-likepeptide-1 (GLP-1) membrane-receptor agonists. They act in aglucose-dependent manner, stimulating insulin secretion only when bloodglucose levels are higher than normal. They also promote β-cellregeneration in animal models. Incretin mimetics decrease gastricmotility and cause nausea. Non-limiting examples: exenatide, exedin-4 orAC2993 (Byetta); liraglutide, NN2211, or NNC 90-1170; it consists of alipid conjugate of GLP-1, with high protein binding and a half-life of˜10 h in man.

DPP-IV inhibitors: affect glucose regulation, inhibiting degradation ofGLP-1. They generally cause fewer problems with hypoglycemia or weightgain as compared to standard treatments. Non-limiting examples:sitagliptin (Januvia); sitagliptin & metformin (Janumet); vildagliptin(Galvus); vildagliptin & metformin (Eucreas).

Sodium-glucose cotransporter 2 (SGLT2) inhibitors: cause a substantialincrease in the amount of glucose that flows out in the urine, thusdecreasing blood glucose levels. They act to control glucose in aninsulin-independent manner Non-limiting example is dapagliflozin(Forxiga).

In one aspect, the at least one additional compound is selected from thegroup consisting of vitamin D, vitamin B complex, vitamin E, vitamin C,ascorbic acid, hyaluronic acid (e.g., 1.2 million Dalton), vitamin Bcomplex, L-carnitine, creatine, lycine, taurine, L-arginine,resveratrol, a salt thereof, and any combinations thereof.

In one embodiment, meglumine and the at least one additional compoundhave synergistic properties within the methods of the invention. Asynergistic effect may be calculated, for example, using suitablemethods such as, for example, the Sigmoid-Emax equation (Holford &Scheiner, 1981, Clin. Pharmacokinet. 6:429-453), the equation of Loeweadditivity (Loewe & Muischnek, 1926, Arch. Exp. Pathol Pharmacol.114:313-326) and the median-effect equation (Chou & Talalay, 1984, Adv.Enzyme Regul. 22:27-55). Each equation referred to above may be appliedto experimental data to generate a corresponding graph to aid inassessing the effects of the compound combination. The correspondinggraphs associated with the equations referred to above are theconcentration-effect curve, isobologram curve and combination indexcurve, respectively.

Salts

A composition comprising meglumine or a salt thereof is contemplatedwithin the invention. Meglumine, or other compounds contemplated withinthe invention, may form salts with acids, and such salts are included inthe present invention. In one embodiment, the salts are acceptablenon-toxic salts. The term “salts” embraces addition salts of free acidsuseful within the methods of the invention. The term “acceptable salt”refers to salts that possess toxicity profiles within a range thataffords utility in in vivo applications. Unacceptable salts maynonetheless possess properties such as high crystallinity, which haveutility in the practice of the present invention, such as for exampleutility in process of synthesis, purification or formulation ofcompounds useful within the methods of the invention.

Suitable acceptable acid addition salts may be prepared from aninorganic acid or from an organic acid. Examples of inorganic acidsinclude sulfate, hydrogen sulfate, hydrochloric, hydrobromic, hydriodic,nitric, carbonic, sulfuric, and phosphoric acids (including hydrogenphosphate and dihydrogen phosphate). Appropriate organic acids may beselected from aliphatic, cycloaliphatic, aromatic, araliphatic,heterocyclic, carboxylic and sulfonic classes of organic acids, examplesof which include formic, acetic, propionic, succinic, glycolic,gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic,fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic,4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic),methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic,trifluoromethanesulfonic, 2-hydroxyethanesulfonic, p-toluenesulfonic,sulfanilic, cyclohexylaminosulfonic, stearic, alginic, β-hydroxybutyric,salicylic, galactaric and galacturonic acid.

Other compounds contemplated within the invention may form salts withbases. Suitable acceptable base addition salts of compounds usefulwithin the invention include, for example, metallic salts includingalkali metal, alkaline earth metal and transition metal salts such as,for example, calcium, magnesium, potassium, sodium and zinc salts.Acceptable base addition salts also include organic salts made frombasic amines such as, for example, N,N′-dibenzylethylene-diamine,chloroprocaine, choline, diethanolamine, ethylenediamine, and procaine.All of these salts may be prepared from the corresponding compound byreacting, for example, the appropriate acid or base with the compound.

Kits

The present invention includes kits for treating or preventingconditions or improving physiological functions as described herein.

In one aspect, the invention includes a kit comprising meglumine or asalt thereof, and an instructional material which describesadministering the meglumine or salt thereof or a composition comprisingthe meglumine or a salt thereof to a cell or an animal. Optionally theinvention further includes a standard. This should be construed toinclude other embodiments of kits that are known to those skilled in theart, such as a kit comprising a (preferably sterile) solvent suitablefor dissolving or suspending the composition of the invention prior toadministering the compound to a cell or an animal. Preferably the animalis a mammal. More preferably, the mammal is a human.

Methods

The invention includes a method of ameliorating or preventing weightgain, promoting weight control, or promoting weight loss in a subject inneed thereof. The method comprises administering to a subject aneffective amount of a composition comprising meglumine or a saltthereof; whereby weight gain in the subject is ameliorated or prevented,or weight control or weight loss in the subject is promoted.

The invention further includes a method of treating or preventingdisregulation of blood glucose levels in a subject in need thereof. Themethod comprises administering to a subject an effective amount of acomposition comprising meglumine or a salt thereof; wherebydisregulation of blood glucose levels in the subject is treated orprevented.

The invention further includes a method of treating or preventing muscleweakness or increasing muscle strength in a subject in need thereof. Themethod comprises administering to a subject an effective amount of acomposition comprising meglumine or a salt thereof; whereby muscleweakness in the subject is treated or prevented, or muscle strength inthe subject is increased.

The invention further includes a method of reducing or preventing theincrease of triglyceride levels in a subject in need thereof. The methodcomprises administering to a subject an effective amount of acomposition comprising meglumine or a salt thereof; whereby the increaseof triglyceride levels in the subject is reduced or prevented.

The invention further includes a method of reducing or preventing theincrease of LDL levels in a subject in need thereof. The methodcomprises administering to a subject an effective amount of acomposition comprising meglumine or a salt thereof; whereby the increaseof LDL levels in the subject is reduced or prevented.

The invention further includes a method of reducing or preventing theincrease of total cholesterol levels in a subject in need thereof. Themethod comprises administering to a subject an effective amount of acomposition comprising meglumine or a salt thereof; whereby the increaseof total cholesterol levels in the subject is reduced or prevented.

The invention further includes a method of reducing or preventing theincrease of levels of a lipoprotein particle apolipoprotein in a subjectin need thereof. The method comprises administering to a subject aneffective amount of a composition comprising meglumine or a saltthereof; whereby the increase of levels of the lipoprotein particle orapolipoprotein in the subject is reduced or prevented.

The invention further includes a method of increasing or preventing thereduction of creatine/albumin levels in a subject in need thereof. Themethod comprises administering to a subject an effective amount of acomposition comprising meglumine or a salt thereof, whereby thecreatine/albumin levels in the subject are increased or the reduction ofthe creatine/albumin levels in the subject is prevented.

The invention further includes a method of increasing longevity orpromoting anti-aging effects in a subject in need thereof. The methodcomprises administering to a subject an effective amount of acomposition comprising meglumine or a salt thereof, whereby longevity inthe subject is increased.

The invention further includes a method of improving the skin conditionin a subject in need thereof. The method comprises administering to asubject an effective amount of a composition comprising meglumine or asalt thereof; whereby the skin condition in the subject is improved.

The invention further comprises a method of improving sexual stamina orperformance in a subject in need thereof. The method comprisesadministering to a subject an effective amount of a compositioncomprising meglumine or a salt thereof; whereby sexual stamina orperformance in the subject is improved.

The invention further comprises a method of increasing vitality orenergy levels in a subject in need thereof. The method comprisesadministering to a subject an effective amount of a compositioncomprising meglumine or a salt thereof; whereby vitality or energylevels in the subject are increased.

The invention further comprises a method of improving the mentalcapacity, or ameliorating or preventing the onset of dementia, in asubject in need thereof. The method comprises administering to a subjectan effective amount of a composition comprising meglumine or a saltthereof; whereby the mental capacity is improved, or the onset ofdementia in the subject is ameliorated or prevented.

The invention further comprises a method of improving or maintainingkidney function in a subject in need thereof. The method comprisesadministering to a subject an effective amount of a compositioncomprising meglumine or a salt thereof;

whereby kidney function in the subject is improved or maintained.

In one embodiment, the composition is administered to the subject by aroute selected from the group consisting of inhalational, oral, rectal,vaginal, parenteral, topical, transdermal, pulmonary, intranasal,buccal, ophthalmic, intrathecal, parenteral, intravenous, and anycombinations thereof. In another embodiment, the composition isadministered to the subject at a frequency selected from the groupconsisting of once a day, twice a day, three times a day, four times aday, once a week, twice a week, three times a week, four times a week,once a month, twice a month, and any combinations thereof. In yetanother embodiment, the composition is administered to the subject at adosage ranging from about 1 ng/kg/application to about 100g/kg/application. In yet another embodiment, the composition isadministered to the subject at a dosage ranging from about 1ng/kg/application to about 100 mg/kg/application. In yet anotherembodiment, the composition is administered to the subject as acontrolled-release formulation. In yet another embodiment, the subjectis a mammal. In yet another embodiment, the mammal is a human. In yetanother embodiment, the subject is further administered medication totreat symptoms of diabetes. In yet another embodiment, the diabetes istype 2 diabetes. In yet another embodiment, the lipoprotein particle orapolipoprotein comprises Apo B, LDL-P, sdLDL, Apo A-I or anycombinations thereof. In yet another embodiment, the lipoproteinparticle or apolipoprotein comprises Apo B, and the Apo B:Apo A-I ratioin the subject is reduced.

Formulations

The compositions useful within the invention is in a form suitable foradministration to a subject, or the composition may further comprise oneor more acceptable carriers, one or more additional ingredients, or somecombination of these. The meglumine may be present in the composition inthe form of a physiologically acceptable salt, such as in combinationwith a physiologically acceptable cation or anion, as is well known inthe art.

In an embodiment, the compositions useful for practicing the method ofthe invention may be administered to deliver a dose of between 1ng/kg/day and 100 mg/kg/day. In another embodiment, the compositionsuseful for practicing the invention may be administered to deliver adose of between 1 ng/kg/day and 500 mg/kg/day.

The relative amounts of the active ingredient, the acceptable carrier,and any additional ingredients in a composition of the invention varies,depending upon the identity, size, and condition of the subject treatedand further depending upon the route by which the composition is to beadministered. By way of example, the composition may comprise between0.1% and 100% (w/w) active ingredient.

Compositions useful in the methods of the invention may be suitablydeveloped for inhalational, oral, rectal, vaginal, parenteral, topical,transdermal, pulmonary, intranasal, buccal, ophthalmic, intrathecal,parenteral, intravenous or another route of administration. Othercontemplated formulations include projected nanoparticles, liposomalpreparations, resealed erythrocytes containing the active ingredient,and immunologically-based formulations. The route(s) of administrationis readily apparent to the skilled artisan and depends upon any numberof factors including the type and severity of the condition beingtreated, the type and age of the veterinary or human patient beingtreated, and the like.

The formulations of the compositions described herein may be prepared byany method known or hereafter developed in the art of pharmacology. Ingeneral, such preparatory methods include the step of bringing theactive ingredient into association with a carrier or one or more otheraccessory ingredients, and then, if necessary or desirable, shaping orpackaging the product into a desired single- or multi-dose unit.

As used herein, a “unit dose” is a discrete amount of the compositioncomprising a predetermined amount of the active ingredient. The amountof the active ingredient is generally equal to the dosage of the activeingredient that would be administered to a subject or a convenientfraction of such a dosage such as, for example, one-half or one-third ofsuch a dosage. The unit dosage form may be for a single daily dose orone of multiple daily doses (for example, about 1 to 4 or more times perday). When multiple daily doses are used, the unit dosage form may bethe same or different for each dose.

Although the descriptions of compositions provided herein areprincipally directed to non-toxic compositions suitable for ethicaladministration to humans, it is understood by the skilled artisan thatsuch compositions are generally suitable for administration to animalsof all sorts. Modification of compositions suitable for administrationto humans in order to render the compositions suitable foradministration to various animals is well understood, and the ordinarilyskilled veterinary pharmacologist can design and perform suchmodification with merely ordinary, if any, experimentation. Subjects towhich administration of the compositions of the invention iscontemplated include, but are not limited to, humans and other primates,mammals including commercially relevant mammals such as cattle, pigs,horses, sheep, cats, and dogs.

In one embodiment, the compositions are formulated using one or moreacceptable non-toxic excipients or carriers. In one embodiment, thecompositions comprise an effective amount of meglumine and an acceptablecarrier. Acceptable carriers, which are useful, include, but are notlimited to, glycerol, water, saline, ethanol and other acceptable saltsolutions such as phosphates and salts of organic acids. Examples ofthese and other acceptable carriers are described in Remington'sPharmaceutical Sciences, 1991, Mack Publication Co., New Jersey.

The carrier may be a solvent or dispersion medium containing, forexample, water, ethanol, polyol (for example, glycerol, propyleneglycol, and liquid polyethylene glycol, and the like), suitable mixturesthereof, and vegetable oils. The proper fluidity may be maintained, forexample, by the use of a coating such as lecithin, by the maintenance ofthe required particle size in the case of dispersion and by the use ofsurfactants. Prevention of the action of microorganisms may be achievedby various antibacterial and antifungal agents, for example, parabens,chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In manycases, it is preferable to include isotonic agents, for example, sugars,sodium chloride, or polyalcohols such as mannitol and sorbitol, in thecomposition. Prolonged absorption of the injectable compositions may bebrought about by including in the composition an agent that delaysabsorption, for example, aluminum monostearate or gelatin.

Formulations may be employed in admixtures with conventional excipients,i.e., acceptable non-toxic organic or inorganic carrier substancessuitable for oral, parenteral, nasal, intravenous, subcutaneous,enteral, or any other suitable mode of administration, known to the art.The preparations may be sterilized and if desired mixed with auxiliaryagents, for example, lubricants, preservatives, stabilizers, wettingagents, emulsifiers, salts for influencing osmotic pressure buffers,coloring, flavoring and/or aromatic substances and the like. They mayalso be combined where desired with other active agents, for example,other analgesic agents.

As used herein, “additional ingredients” include, but are not limitedto, one or more of the following: excipients; surface active agents;dispersing agents; inert diluents; granulating and disintegratingagents; binding agents; lubricating agents; sweetening agents; flavoringagents; coloring agents; preservatives; physiologically degradablecompositions such as gelatin; aqueous vehicles and solvents; oilyvehicles and solvents; suspending agents; dispersing or wetting agents;emulsifying agents, demulcents; buffers; salts; thickening agents;fillers; emulsifying agents; antioxidants; antibiotics; antifungalagents; stabilizing agents; and acceptable polymeric or hydrophobicmaterials. Other “additional ingredients” that may be included in thecompositions of the invention are known in the art and described, forexample, in Genaro, ed., 1985, Remington's Pharmaceutical Sciences, MackPublishing Co., Easton, Pa., which is incorporated herein by reference.

The composition of the invention may comprise a preservative from about0.005% to 2.0% by total weight of the composition. The preservative isused to prevent spoilage in the case of exposure to contaminants in theenvironment. Examples of preservatives useful in accordance with theinvention included, but are not limited to, those selected from thegroup consisting of benzyl alcohol, sorbic acid, parabens, imidurea andcombinations thereof. A particularly preferred preservative is acombination of about 0.5% to 2.0% benzyl alcohol and 0.05% to 0.5%sorbic acid.

The composition preferably includes an antioxidant and a chelating agentthat inhibit the degradation of the compound. Preferred antioxidants forsome compounds are BHT, BHA, alpha-tocopherol and ascorbic acid in thepreferred range of about 0.01% to 0.3% and more preferably BHT in therange of 0.03% to 0.1% by weight by total weight of the composition.Preferably, the chelating agent is present in an amount of from 0.01% to0.5% by weight by total weight of the composition. Particularlypreferred chelating agents include edetate salts (for example, disodiumedetate) and citric acid in the weight range of about 0.01% to 0.20% andmore preferably in the range of 0.02% to 0.10% by weight by total weightof the composition. The chelating agent is useful for chelating metalions in the composition, which may be detrimental to the shelf life ofthe formulation. While BHT and disodium edetate are the particularlypreferred antioxidant and chelating agent respectively for somecompounds, other suitable and equivalent antioxidants and chelatingagents may be substituted therefore as would be known to those skilledin the art.

Liquid suspensions may be prepared using conventional methods to achievesuspension of the active ingredient in an aqueous or oily vehicle.Aqueous vehicles include, for example, water, and isotonic saline. Oilyvehicles include, for example, almond oil, oily esters, ethyl alcohol,vegetable oils such as arachis, olive, sesame, or coconut oil,fractionated vegetable oils, and mineral oils such as liquid paraffin.Liquid suspensions may further comprise one or more additionalingredients including, but not limited to, suspending agents, dispersingor wetting agents, emulsifying agents, demulcents, preservatives,buffers, salts, flavorings, coloring agents, and sweetening agents. Oilysuspensions may further comprise a thickening agent. Known suspendingagents include, but are not limited to, sorbitol syrup, hydrogenatededible fats, sodium alginate, polyvinylpyrrolidone, gum tragacanth, gumacacia, and cellulose derivatives such as sodium carboxymethylcellulose,methylcellulose, hydroxypropylmethylcellulose. Known dispersing orwetting agents include, but are not limited to, naturally-occurringphosphatides such as lecithin, condensation products of an alkyleneoxide with a fatty acid, with a long chain aliphatic alcohol, with apartial ester derived from a fatty acid and a hexitol, or with a partialester derived from a fatty acid and a hexitol anhydride (for example,polyoxyethylene stearate, heptadecaethyleneoxycetanol, polyoxyethylenesorbitol monooleate, and polyoxyethylene sorbitan monooleate,respectively). Known emulsifying agents include, but are not limited to,lecithin, and acacia. Known preservatives include, but are not limitedto, methyl, ethyl, or n-propyl para-hydroxybenzoates, ascorbic acid, andsorbic acid. Known sweetening agents include, for example, glycerol,propylene glycol, sorbitol, sucrose, and saccharin. Known thickeningagents for oily suspensions include, for example, beeswax, hardparaffin, and cetyl alcohol.

Liquid solutions of the active ingredient in aqueous or oily solventsmay be prepared in substantially the same manner as liquid suspensions,the primary difference being that the active ingredient is dissolved,rather than suspended in the solvent. As used herein, an “oily” liquidis one that comprises a carbon-containing liquid molecule and whichexhibits a less polar character than water. Liquid solutions of thecomposition of the invention may comprise each of the componentsdescribed with regard to liquid suspensions, it being understood thatsuspending agents will not necessarily aid dissolution of the activeingredient in the solvent. Aqueous solvents include, for example, water,and isotonic saline. Oily solvents include, for example, almond oil,oily esters, ethyl alcohol, vegetable oils such as arachis, olive,sesame, or coconut oil, fractionated vegetable oils, and mineral oilssuch as liquid paraffin.

Powdered and granular formulations of a preparation of the invention maybe prepared using known methods. Such formulations may be administereddirectly to a subject, used, for example, to form tablets, to fillcapsules, or to prepare an aqueous or oily suspension or solution byaddition of an aqueous or oily vehicle thereto. Each of theseformulations may further comprise one or more of dispersing or wettingagent, a suspending agent, and a preservative. Additional excipients,such as fillers and sweetening, flavoring, or coloring agents, may alsobe included in these formulations.

A composition of the invention may also be prepared, packaged, or soldin the form of oil-in-water emulsion or a water-in-oil emulsion. Theoily phase may be a vegetable oil such as olive or arachis oil, amineral oil such as liquid paraffin, or a combination of these. Suchcompositions may further comprise one or more emulsifying agents such asnaturally occurring gums such as gum acacia or gum tragacanth,naturally-occurring phosphatides such as soybean or lecithinphosphatide, esters or partial esters derived from combinations of fattyacids and hexitol anhydrides such as sorbitan monooleate, andcondensation products of such partial esters with ethylene oxide such aspolyoxyethylene sorbitan monooleate. These emulsions may also containadditional ingredients including, for example, sweetening or flavoringagents.

Methods for impregnating or coating a material with a chemicalcomposition are known in the art, and include, but are not limited tomethods of depositing or binding a chemical composition onto a surface,methods of incorporating a chemical composition into the structure of amaterial during the synthesis of the material (i.e., such as with aphysiologically degradable material), and methods of absorbing anaqueous or oily solution or suspension into an absorbent material, withor without subsequent drying.

Administration/Dosing

The regimen of administration may affect what constitutes an effectiveamount. For example, the therapeutic formulations may be administered tothe patient either prior to or after diagnosis of any of the condition scontemplated herein, or to affect or improve any of the physiologicalfunctions contemplated herein. Further, several divided dosages, as wellas staggered dosages may be administered daily or sequentially, or thedose may be continuously infused, or may be a bolus injection. Further,the dosages of the therapeutic formulations may be proportionallyincreased or decreased as indicated by the exigencies of the therapeuticor prophylactic situation.

Administration of the compositions of the present invention to apatient, preferably a mammal, more preferably a human, may be carriedout using known procedures, at dosages and for periods of time effectiveto treat the condition s contemplated herein in the patient. Aneffective amount of the therapeutic compound necessary to achieve atherapeutic effect may vary according to factors such as the activity ofthe particular compound employed; the time of administration; the rateof excretion of the compound; the duration of the treatment; otherdrugs, compounds or materials used in combination with the compound; thestate of the condition, age, sex, weight, condition, general health andprior medical history of the patient being treated, and like factorswell-known in the art. Dosage regimens may be adjusted to provide theoptimum therapeutic response. For example, several divided doses may beadministered daily or the dose may be proportionally reduced asindicated by the exigencies of the therapeutic situation. A non-limitingexample of an effective dose range for a therapeutic compound of theinvention is from about 0.01 and 50 mg/kg of body weight/per day. One ofordinary skill in the art would be able to study the relevant factorsand make the determination regarding the effective amount of thetherapeutic compound without undue experimentation.

The compound can be administered to an animal as frequently as severaltimes daily, or it may be administered less frequently, such as once aday, once a week, once every two weeks, once a month, or even lessfrequently, such as once every several months or even once a year orless. It is understood that the amount of compound dosed per day may beadministered, in non-limiting examples, every day, every other day,every 2 days, every 3 days, every 4 days, or every 5 days. For example,with every other day administration, a 5 mg per day dose may beinitiated on Monday with a first subsequent 5 mg per day doseadministered on Wednesday, a second subsequent 5 mg per day doseadministered on Friday, and so on. The frequency of the dose is readilyapparent to the skilled artisan and depends upon any number of factors,such as, but not limited to, the type and severity of the conditionbeing treated, and the type and age of the animal.

Actual dosage levels of the active ingredients in compositions of thisinvention may be varied so as to obtain an amount of the activeingredient that is effective to achieve the desired response for aparticular patient, composition, and mode of administration, withoutbeing toxic to the patient.

In particular embodiments, it is especially advantageous to formulatethe compound in dosage unit form for ease of administration anduniformity of dosage. Dosage unit form as used herein refers tophysically discrete units suited as unitary dosages for the patients tobe treated; each unit containing a predetermined quantity of therapeuticcompound calculated to produce the desired therapeutic effect inassociation with the required vehicle. The dosage unit forms of theinvention are dictated by and directly dependent on (a) the uniquecharacteristics of the therapeutic compound and the particulartherapeutic effect to be achieved, and (b) the limitations inherent inthe art of compounding/formulating such a therapeutic compound for thetreatment of platelet hyperactivity in a patient.

In one embodiment, the compositions of the invention are administered tothe patient in dosages that range from one to five times per day ormore. In another embodiment, the compositions of the invention areadministered to the patient in range of dosages that include, but arenot limited to, once every day, every two, days, every three days toonce a week, and once every two weeks. It is readily apparent to oneskilled in the art that the frequency of administration of the variouscombination compositions of the invention varies from subject to subjectdepending on many factors including, but not limited to, age, conditionto be treated, gender, overall health, and other factors. Thus, theinvention should not be construed to be limited to any particular dosageregime and the precise dosage and composition to be administered to anypatient will be determined by the attending physical taking all otherfactors about the patient into account.

Compounds of the invention for administration may be in the range offrom about 1 μg to about 7,500 mg, about 20 μg to about 7,000 mg, about40 μg to about 6,500 mg, about 80 μg to about 6,000 mg, about 100 μg toabout 5,500 mg, about 200 μg to about 5,000 mg, about 400 μg to about4,000 mg, about 800 μg to about 3,000 mg, about 1 mg to about 2,500 mg,about 2 mg to about 2,000 mg, about 5 mg to about 1,000 mg, about 10 mgto about 750 mg, about 20 mg to about 600 mg, about 30 mg to about 500mg, about 40 mg to about 400 mg, about 50 mg to about 300 mg, about 60mg to about 250 mg, about 70 mg to about 200 mg, about 80 mg to about150 mg, and any and all whole or partial increments therebetween.

In some embodiments, the dose of a compound of the invention is fromabout 0.5 μg and about 5,000 mg. In some embodiments, a dose of acompound of the invention used in compositions described herein is lessthan about 5,000 mg, or less than about 4,000 mg, or less than about3,000 mg, or less than about 2,000 mg, or less than about 1,000 mg, orless than about 800 mg, or less than about 600 mg, or less than about500 mg, or less than about 200 mg, or less than about 50 mg. Similarly,in some embodiments, a dose of a second compound as described herein isless than about 1,000 mg, or less than about 800 mg, or less than about600 mg, or less than about 500 mg, or less than about 400 mg, or lessthan about 300 mg, or less than about 200 mg, or less than about 100 mg,or less than about 50 mg, or less than about 40 mg, or less than about30 mg, or less than about 25 mg, or less than about 20 mg, or less thanabout 15 mg, or less than about 10 mg, or less than about 5 mg, or lessthan about 2 mg, or less than about 1 mg, or less than about 0.5 mg, andany and all whole or partial increments thereof.

In one embodiment, the present invention is directed to a packagedcomposition comprising a container holding a therapeutically effectiveamount of a compound of the invention, alone or in combination with asecond agent; and instructions for using the compound to treat, prevent,or reduce the conditions contemplated herein in a patient.

The term “container” includes any receptacle for holding thecomposition. For example, in one embodiment, the container is thepackaging that contains the composition. In other embodiments, thecontainer is not the packaging that contains the composition, i.e., thecontainer is a receptacle, such as a box or vial that contains thepackaged composition or unpackaged composition and the instructions foruse of the composition. Moreover, packaging techniques are well known inthe art. It should be understood that the instructions for use of thecomposition may be contained on the packaging containing thecomposition, and as such the instructions form an increased functionalrelationship to the packaged product. However, it should be understoodthat the instructions may contain information pertaining to thecompound's ability to perform its intended function, for example,treating, preventing, or reducing the conditions contemplated herein.

Routes of Administration

Routes of administration of any of the compositions of the inventioninclude inhalational, oral, nasal, rectal, parenteral, sublingual,transdermal, transmucosal (for example, sublingual, lingual,(trans)buccal, (trans)urethral, vaginal (for example, trans- andperivaginally), (intra)nasal, and (trans)rectal), intravesical,intrapulmonary, intraduodenal, intragastrical, intrathecal,subcutaneous, intramuscular, intradermal, intra-arterial, intravenous,intrabronchial, inhalation, and topical administration.

Suitable compositions and dosage forms include, for example, tablets,capsules, caplets, pills, gel caps, troches, dispersions, suspensions,solutions, syrups, granules, beads, transdermal patches, gels, powders,pellets, magmas, lozenges, creams, pastes, plasters, lotions, discs,suppositories, liquid sprays for nasal or oral administration, drypowder or aerosolized formulations for inhalation, compositions andformulations for intravesical administration and the like. It should beunderstood that the formulations and compositions that would be usefulin the present invention are not limited to the particular formulationsand compositions that are described herein.

Oral Administration

For oral application, particularly suitable are tablets, dragees,liquids, drops, suppositories, or capsules, caplets and gel caps. Otherformulations suitable for oral administration include, but are notlimited to, a powdered or granular formulation, an aqueous or oilysuspension, an aqueous or oily solution, a paste, a gel, toothpaste, amouthwash, a coating, an oral rinse, or an emulsion. The compositionsintended for oral use may be prepared according to any method known inthe art and such compositions may contain one or more agents selectedfrom the group consisting of inert, non-toxic excipients suitable forthe manufacture of tablets. Such excipients include, for example, aninert diluent such as lactose; granulating and disintegrating agentssuch as cornstarch; binding agents such as starch; and lubricatingagents such as magnesium stearate.

Tablets may be non-coated or they may be coated using known methods toachieve delayed disintegration in the gastrointestinal tract of asubject, thereby providing sustained release and absorption of theactive ingredient. By way of example, a material such as glycerylmonostearate or glyceryl distearate may be used to coat tablets. Furtherby way of example, tablets may be coated using methods described in U.S.Pat. Nos. 4,256,108; 4,160,452; and U.S. Pat. No. 4,265,874 to formosmotically controlled release tablets. Tablets may further comprise asweetening agent, a flavoring agent, a coloring agent, a preservative,or some combination of these in order to provide for a non-toxic,elegant and palatable preparation.

Hard capsules comprising the active ingredient may be made using aphysiologically degradable composition, such as gelatin. Such hardcapsules comprise the active ingredient, and may further compriseadditional ingredients including, for example, an inert solid diluentsuch as calcium carbonate, calcium phosphate, or kaolin.

Soft gelatin capsules comprising the active ingredient may be made usinga physiologically degradable composition, such as gelatin. Such softcapsules comprise the active ingredient, which may be mixed with wateror an oil medium such as peanut oil, liquid paraffin, or olive oil.

For oral administration, the compounds of the invention may be in theform of tablets or capsules prepared by conventional means withnon-toxic acceptable excipients such as binding agents; fillers;lubricants; disintegrates; or wetting agents. If desired, the tabletsmay be coated using suitable methods and coating materials such asOPADRY™ film coating systems available from Colorcon, West Point, Pa.(for example, OPADRY™ OY Type, OYC Type, Organic Enteric OY-P Type,Aqueous Enteric OY-A Type, OY-PM Type and OPADRY™ White, 32K18400).

Liquid preparation for oral administration may be in the form ofsolutions, syrups or suspensions. The liquid preparations may beprepared by conventional means with acceptable non-toxic additives suchas suspending agents (for example, sorbitol syrup, methyl cellulose orhydrogenated edible fats); emulsifying agent (for example, lecithin oracacia); non-aqueous vehicles (for example, almond oil, oily esters orethyl alcohol); and preservatives (for example, methyl or propylpara-hydroxy benzoates or sorbic acid). Liquid formulations of anon-toxic composition of the invention which are suitable for oraladministration may be prepared, packaged, and sold either in liquid formor in the form of a dry product intended for reconstitution with wateror another suitable vehicle prior to use.

A tablet comprising the active ingredient may, for example, be made bycompressing or molding the active ingredient, optionally with one ormore additional ingredients. Compressed tablets may be prepared bycompressing, in a suitable device, the active ingredient in afree-flowing form such as a powder or granular preparation, optionallymixed with one or more of a binder, a lubricant, an excipient, a surfaceactive agent, and a dispersing agent. Molded tablets may be made bymolding, in a suitable device, a mixture of the active ingredient, anacceptable non-toxic carrier, and at least sufficient liquid to moistenthe mixture. Acceptable excipients used in the manufacture of tabletsinclude, but are not limited to, inert diluents, granulating anddisintegrating agents, binding agents, and lubricating agents. Knowndispersing agents include, but are not limited to, potato starch andsodium starch glycolate. Known surface-active agents include, but arenot limited to, sodium lauryl sulphate. Known diluents include, but arenot limited to, calcium carbonate, sodium carbonate, lactose,microcrystalline cellulose, calcium phosphate, calcium hydrogenphosphate, and sodium phosphate. Known granulating and disintegratingagents include, but are not limited to, corn starch and alginic acid.Known binding agents include, but are not limited to, gelatin, acacia,pre-gelatinized maize starch, polyvinylpyrrolidone, and hydroxypropylmethylcellulose. Known lubricating agents include, but are not limitedto, magnesium stearate, stearic acid, silica, and talc.

Granulating techniques are well known in the art for modifying startingpowders or other particulate materials of an active ingredient. Thepowders are typically mixed with a binder material into larger permanentfree-flowing agglomerates or granules referred to as a “granulation.”For example, solvent-using “wet” granulation processes are generallycharacterized in that the powders are combined with a binder materialand moistened with water or an organic solvent under conditionsresulting in the formation of a wet granulated mass from which thesolvent must then be evaporated.

Melt granulation generally consists in the use of materials that aresolid or semi-solid at room temperature (i.e. having a relatively lowsoftening or melting point range) to promote granulation of powdered orother materials, essentially in the absence of added water or otherliquid solvents. The low melting solids, when heated to a temperature inthe melting point range, liquefy to act as a binder or granulatingmedium. The liquefied solid spreads itself over the surface of powderedmaterials with which it is contacted, and on cooling, forms a solidgranulated mass in which the initial materials are bound together. Theresulting melt granulation may then be provided to a tablet press or beencapsulated for preparing the oral dosage form. Melt granulationimproves the dissolution rate and bioavailability of an active compoundby forming a solid dispersion or solid solution.

U.S. Pat. No. 5,169,645 discloses directly compressible wax-containinggranules having improved flow properties. The granules are obtained whenwaxes are admixed in the melt with certain flow improving additives,followed by cooling and granulation of the admixture. In certainembodiments, only the wax itself melts in the melt combination of thewax(es) and additives(s), and in other cases both the wax(es) and theadditives(s) will melt.

The present invention also includes a multi-layer tablet comprising alayer providing for the delayed release of one or more compounds usefulwithin the methods of the invention, and a further layer providing forthe immediate release of one or more compounds useful within the methodsof the invention. Using a wax/pH-sensitive polymer mix, a gastricinsoluble composition may be obtained in which the active ingredient isentrapped, ensuring its delayed release.

Parenteral Administration

As used herein, “parenteral administration” of a composition includesany route of administration characterized by physical breaching of atissue of a subject and administration of the composition through thebreach in the tissue. Parenteral administration thus includes, but isnot limited to, administration of a composition by injection of thecomposition, by application of the composition through a surgicalincision, by application of the composition through a tissue-penetratingnon-surgical wound, and the like. In particular, parenteraladministration is contemplated to include, but is not limited to,subcutaneous, intravenous, intraperitoneal, intramuscular, intrasternalinjection, and kidney dialytic infusion techniques.

Formulations of a composition suitable for parenteral administrationcomprise the active ingredient combined with an acceptable carrier, suchas sterile water or sterile isotonic saline. Such formulations may beprepared, packaged, or sold in a form suitable for bolus administrationor for continuous administration. Injectable formulations may beprepared, packaged, or sold in unit dosage form, such as in ampules orin multidose containers containing a preservative. Formulations forparenteral administration include, but are not limited to, suspensions,solutions, emulsions in oily or aqueous vehicles, pastes, andimplantable sustained-release or biodegradable formulations. Suchformulations may further comprise one or more additional ingredientsincluding, but not limited to, suspending, stabilizing, or dispersingagents. In one embodiment of a formulation for parenteraladministration, the active ingredient is provided in dry (i.e., powderor granular) form for reconstitution with a suitable vehicle (forexample, sterile pyrogen-free water) prior to parenteral administrationof the reconstituted composition.

The compositions may be prepared, packaged, or sold in the form of asterile injectable aqueous or oily suspension or solution. Thissuspension or solution may be formulated according to the known art, andmay comprise, in addition to the active ingredient, additionalingredients such as the dispersing agents, wetting agents, or suspendingagents described herein. Such sterile injectable formulations may beprepared using a non-toxic parenterally-acceptable diluent or solvent,such as water or 1,3-butanediol, for example. Other acceptable diluentsand solvents include, but are not limited to, Ringer's solution,isotonic sodium chloride solution, and fixed oils such as syntheticmono- or diglycerides. Other parentally-administrable formulationsuseful include those which comprise the active ingredient inmicrocrystalline form, in a liposomal preparation, or as a component ofa biodegradable polymer system. Compositions for sustained release orimplantation may comprise acceptable non-toxic polymeric or hydrophobicmaterials such as an emulsion, an ion exchange resin, a sparinglysoluble polymer, or a sparingly soluble salt.

Topical Administration

An obstacle for topical administration of compositions is the stratumcorneum layer of the epidermis. The stratum corneum is a highlyresistant layer comprised of protein, cholesterol, sphingolipids, freefatty acids and various other lipids, and includes cornified and livingcells. One of the factors that limit the penetration rate (flux) of acompound through the stratum corneum is the amount of the activesubstance that can be loaded or applied onto the skin surface. Thegreater the amount of active substance applied per unit of area of theskin, the greater the concentration gradient between the skin surfaceand the lower layers of the skin, and in turn the greater the diffusionforce of the active substance through the skin. Therefore, a formulationcontaining a greater concentration of the active substance is morelikely to result in penetration of the active substance through theskin, and more of it, and at a more consistent rate, than a formulationhaving a lesser concentration, all other things being equal.

Formulations suitable for topical administration include, but are notlimited to, liquid or semi-liquid preparations such as liniments,lotions, oil-in-water or water-in-oil emulsions such as creams,ointments or pastes, and solutions or suspensions. Topicallyadministrable formulations may, for example, comprise from about 1% toabout 10% (w/w) active ingredient, although the concentration of theactive ingredient may be as high as the solubility limit of the activeingredient in the solvent. Formulations for topical administration mayfurther comprise one or more of the additional ingredients describedherein.

Enhancers of permeation may be used. These materials increase the rateof penetration of compounds across the skin. Typical enhancers in theart include ethanol, glycerol monolaurate, PGML (polyethylene glycolmonolaurate), dimethylsulfoxide, and the like. Other enhancers includeoleic acid, oleyl alcohol, ethoxydiglycol, laurocapram, alkanecarboxylicacids, polar lipids, or N-methyl-2-pyrrolidone.

One acceptable vehicle for topical delivery of some of the compositionsof the invention may contain liposomes. The composition of the liposomesand their use are known in the art (for example, U.S. Pat. No.6,323,219).

In alternative embodiments, the topically active composition may beoptionally combined with other ingredients such as adjuvants,anti-oxidants, chelating agents, surfactants, foaming agents, wettingagents, emulsifying agents, viscosifiers, buffering agents,preservatives, and the like. In another embodiment, a permeation orpenetration enhancer is included in the composition and is effective inimproving the percutaneous penetration of the active ingredient into andthrough the stratum corneum with respect to a composition lacking thepermeation enhancer. Various permeation enhancers, including oleic acid,oleyl alcohol, ethoxydiglycol, laurocapram, alkanecarboxylic acids,dimethylsulfoxide, polar lipids, or N-methyl-2-pyrrolidone, are known tothose of skill in the art. In another aspect, the composition mayfurther comprise a hydrotropic agent, which functions to increasedisorder in the structure of the stratum corneum, and thus allowsincreased transport across the stratum corneum. Various hydrotropicagents such as isopropyl alcohol, propylene glycol, or sodium xylenesulfonate, are known to those of skill in the art.

The topically active composition should be applied in an amounteffective to affect desired changes. As used herein “amount effective”shall mean an amount sufficient to cover the region of skin surfacewhere a change is desired. An active compound should be present in theamount of from about 0.0001% to about 15% by weight volume of thecomposition. More preferable, it should be present in an amount fromabout 0.0005% to about 5% of the composition; most preferably, it shouldbe present in an amount of from about 0.001% to about 1% of thecomposition. Such compounds may be synthetically-or naturally derived.

Buccal Administration

A composition of the invention may be prepared, packaged, or sold in aformulation suitable for buccal administration. Such formulations may,for example, be in the form of tablets or lozenges made usingconventional methods, and may contain, for example, 0.1 to 20% (w/w) ofthe active ingredient, the balance comprising an orally dissolvable ordegradable composition and, optionally, one or more of the additionalingredients described herein. Alternately, formulations suitable forbuccal administration may comprise a powder or an aerosolized oratomized solution or suspension comprising the active ingredient. Suchpowdered, aerosolized, or aerosolized formulations, when dispersed,preferably have an average particle or droplet size in the range fromabout 0.1 to about 200 nanometers, and may further comprise one or moreof the additional ingredients described herein. The examples offormulations described herein are not exhaustive and it is understoodthat the invention includes additional modifications of these and otherformulations not described herein, but which are known to those of skillin the art.

Rectal Administration

A composition of the invention may be prepared, packaged, or sold in aformulation suitable for rectal administration. Such a composition maybe in the form of, for example, a suppository, a retention enemapreparation, and a solution for rectal or colonic irrigation.

Suppository formulations may be made by combining the active ingredientwith a non-irritating acceptable excipient which is solid at ordinaryroom temperature (i.e., about 20° C.) and which is liquid at the rectaltemperature of the subject (i.e., about 37° C. in a healthy human).Suitable non-toxic acceptable excipients include, but are not limitedto, cocoa butter, polyethylene glycols, and various glycerides.Suppository formulations may further comprise various additionalingredients including, but not limited to, antioxidants, andpreservatives.

Retention enema preparations or solutions for rectal or colonicirrigation may be made by combining the active ingredient with anon-toxic acceptable liquid carrier. As is well known in the art, enemapreparations may be administered using, and may be packaged within, adelivery device adapted to the rectal anatomy of the subject. Enemapreparations may further comprise various additional ingredientsincluding, but not limited to, antioxidants, and preservatives.

Additional Administration Forms

Additional dosage forms of this invention include dosage forms asdescribed in U.S. Pat. Nos. 6,340,475, 6,488,962, 6,451,808, 5,972,389,5,582,837, and 5,007,790. Additional dosage forms of this invention alsoinclude dosage forms as described in U.S. Patent Applications Nos.20030147952, 20030104062, 20030104053, 20030044466, 20030039688, and20020051820. Additional dosage forms of this invention also includedosage forms as described in PCT Applications Nos. WO 03/35041, WO03/35040, WO 03/35029, WO 03/35177, WO 03/35039, WO 02/96404, WO02/32416, WO 01/97783, WO 01/56544, WO 01/32217, WO 98/55107, WO98/11879, WO 97/47285, WO 93/18755, and WO 90/11757.

Controlled Release Formulations and Delivery Systems

Controlled- or sustained-release formulations of a non-toxic compositionof the invention may be made using conventional technology. In somecases, the dosage forms to be used can be provided as slow orcontrolled-release of one or more active ingredients therein using, forexample, hydropropylmethyl cellulose, other polymer matrices, gels,permeable membranes, osmotic systems, multilayer coatings,microparticles, liposomes, or microspheres or a combination thereof toprovide the desired release profile in varying proportions. Suitablecontrolled-release formulations known to those of ordinary skill in theart, including those described herein, may be readily selected for usewith the compositions of the invention. Thus, single unit dosage formssuitable for oral administration, such as tablets, capsules, gel caps,and caplets, that are adapted for controlled-release are encompassed bythe present invention.

Most controlled-release products have a common goal of improving therapyover that achieved by their non-controlled counterparts. Ideally, theuse of an optimally designed controlled-release preparation in treatmentis characterized by a minimum of substance being employed to cure orcontrol the condition in a minimum amount of time. Advantages ofcontrolled-release formulations include extended activity of thecompound, reduced dosage frequency, and increased subject compliance. Inaddition, controlled-release formulations can be used to affect the timeof onset of action or other characteristics, such as blood level of thecompound, and thus can affect the occurrence of side effects.

Most controlled-release formulations are designed to initially releasean amount of compound that promptly produces the desired therapeuticeffect, and gradually and continually release of other amounts ofcompound to maintain this level of therapeutic effect over an extendedperiod of time. In order to maintain this constant level of compound inthe body, the compound must be released from the dosage form at a ratethat will replace the amount of compound being metabolized and excretedfrom the body.

Controlled-release of an active ingredient can be stimulated by variousinducers, for example, pH, temperature, enzymes, water, or otherphysiological conditions or compounds. The term “controlled-releasecomponent” in the context of the present invention is defined herein asa compound or compounds, including, but not limited to, polymers,polymer matrices, gels, permeable membranes, liposomes, or microspheresor a combination thereof that facilitates the controlled-release of theactive ingredient.

In certain embodiments, the formulations of the present invention maybe, but are not limited to, short-term, rapid-offset, as well ascontrolled, for example, sustained release, delayed release andpulsatile release formulations.

The term sustained release is used in its conventional sense to refer toa formulation that provides for gradual release of a compound over anextended period of time, and that may, although not necessarily, resultin substantially constant blood levels of a compound over an extendedtime period. The period of time may be as long as a month or more andshould be a release which is longer that the same amount of agentadministered in bolus form. For sustained release, the compounds may beformulated with a suitable polymer or hydrophobic material whichprovides sustained release properties to the compounds. As such, thecompounds for use the method of the invention may be administered in theform of microparticles, for example, by injection or in the form ofwafers or discs by implantation. In a preferred embodiment of theinvention, the compounds of the invention are administered to a patient,alone or in combination with another agent, using a sustained releaseformulation.

The term delayed release is used herein in its conventional sense torefer to a formulation that provides for an initial release of thecompound after some delay following compound administration and thatmat, although not necessarily, includes a delay of from about 10 minutesup to about 12 hours. The term pulsatile release is used herein in itsconventional sense to refer to a formulation that provides release ofthe compound in such a way as to produce pulsed plasma profiles of thecompound after compound administration. The term immediate release isused in its conventional sense to refer to a formulation that providesfor release of the compound immediately after compound administration.

As used herein, short-term refers to any period of time up to andincluding about 8 hours, about 7 hours, about 6 hours, about 5 hours,about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40minutes, about 20 minutes, or about 10 minutes and any or all whole orpartial increments thereof after compound administration.

As used herein, rapid-offset refers to any period of time up to andincluding about 8 hours, about 7 hours, about 6 hours, about 5 hours,about 4 hours, about 3 hours, about 2 hours, about 1 hour, about 40minutes, about 20 minutes, or about 10 minutes, and any and all whole orpartial increments thereof after compound administration.

In accordance with the present invention, as described above or asdiscussed in the Examples below, there can be employed conventionalchemical, cellular, histochemical, biochemical, molecular biology,microbiology and recombinant DNA techniques which are known to those ofskill in the art. Such techniques are explained fully in the literature.See for example, Sambrook et al., 1989 Molecular Cloning—a LaboratoryManual, Cold Spring Harbor Press; Glover, (1985) DNA Cloning: aPractical Approach; Gait, (1984) Oligonucleotide Synthesis; Harlow etal., 1988 Antibodies—a Laboratory Manual, Cold Spring Harbor Press; Roeet al., 1996 DNA Isolation and Sequencing: Essential Techniques, JohnWiley; and Ausubel et al., 1995 Current Protocols in Molecular Biology,Greene Publishing.

Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, numerous equivalents to thespecific procedures, embodiments, claims, and examples described herein.Such equivalents were considered to be within the scope of thisinvention and covered by the claims appended hereto. For example, itshould be understood, that modifications in reaction conditions,including but not limited to reaction times, reaction size/volume, andexperimental reagents, such as solvents, catalysts, pressures,atmospheric conditions, e.g., nitrogen atmosphere, andreducing/oxidizing agents, with art-recognized alternatives and using nomore than routine experimentation, are within the scope of the presentapplication.

It is to be understood that wherever values and ranges are providedherein, all values and ranges encompassed by these values and ranges,are meant to be encompassed within the scope of the present invention.Moreover, all values that fall within these ranges, as well as the upperor lower limits of a range of values, are also contemplated by thepresent application.

The following examples further illustrate aspects of the presentinvention. However, they are in no way a limitation of the teachings ordisclosure of the present invention as set forth herein.

EXAMPLES

The invention is now described with reference to the following Examples.These Examples are provided for the purpose of illustration only, andthe invention is not limited to these Examples, but rather encompassesall variations that are evident as a result of the teachings providedherein.

Grip Strength Test

The grip strength test is a widely-used non-invasive method designed toevaluate mouse limb strength that has been used to investigate theeffects of neuromuscular disorders and compound under testing. It isbased on the natural tendency of the mouse to grasp a bar or grid whenit is suspended by the tail. During this test the mouse grips with bothforelimbs (or hind-limbs) a single bar or a mesh.

There are three kinds of grip strength tests used: Mesh Grip Test, WireGrip Test, and Automatic Grip Strength (GS Meter). The Mesh Grip Testmeasures the ability of the mouse to remain clinging to an inverted ortilted surface such as a wire grid or a cage lid for a period of time,usually up to 1 minute; the Wire Grip Test measures the ability of themouse to hang on a wire with its forepaws for a preset length of time oruntil grip fails, while in the Automatic Grip Strength the mouse graspsa horizontal metal bar or grid while is pulled by the tail. The bar orgrid is attached to a force transducer that peak pull-force achieved onits digital display.

This method can be used to measure condition progression andneurobehaviour as well as to test effect of specific therapeuticinterventions in mouse models of neuromuscular disorders; increases ingrip strength have been interpreted as evidence of increased musclestrength.

The grip strength test is useful to assess strength in animal models ofspinal muscular atrophy (SMA) and the effect of experimental therapies.This test can be performed reliably in SMA mice starting at 2-4 weeks oflife (mesh grip≥postnatal day 12 (P12); bar test≥P10; automated≥P28).Since this is an in vivo behavioural test, by its nature, it hasvariability. In carefully controlled conditions, the variability withina group of animals of similar gender, age, and genotype should rangebetween 10-25%. A similar variability should be observed among repeatedmeasures (3 to 5) performed in the same animal during the trial.

Example 1: Mice Study

A group of sixteen C57BL/6 male mice at 12 weeks of age were distributedinto 4 groups (n=4 each). Animals were fed a normal diet supplementedwith 0 mM, 10 mM, 40 mM, or 75 mM meglumine in the drinking water. Theapproximate doses of meglumine were 537 mg/kg/day, 2,146 mg/kg/day, and4,027 mg/kg/day for animals treated with, respectfully, 10 mM, 40 mM and75 mM meglumine.

Animals were observed daily, and date of death was noted if applicable.Four animals were found dead in their cages, and twelve were euthanizedafter showing symptoms of distress (hunched posture, weight loss,decreased food intake).

Animal Weights:

Animals were weighed weekly, and their average weight is illustrated inFIG. 1. For all groups, animals gained weight from weeks 12-52,maintained a relatively stable weight from weeks 42-84, and decreasedweight after week 92. Certain animals showed marked weight loss justprior to death. The group that received water without meglumine weighedslightly less than the animals in the meglumine treated groups at thestart of the study, and this persisted for the study duration. Animalstreated with meglumine weighed more than the controls, but the increasewas not dose-dependent.

Urine 3-Deoxyglucosone (3DG) Levels:

Urine was collected from animals (n=3 for all groups, except n=4 for 75mM meglumine) at the age of 103 weeks and 3DG levels were measured usingGC-MS with an internal U-[¹³C]-3DG standard (FIG. 2). Prior to analysis,urine samples were treated with 2,3-diaminonapthalene overnight toderivatize 3DG, and then extracted with ethyl acetate. Urinarycreatinine levels were measured with a reagent kit from OxfordBiochemicals. The 3DG/creatinine ratio (±standard deviation) isillustrated in FIG. 2. The ratio for all meglumine treated animals wasless than the control animals.

Longevity:

The average lifespan (±standard deviation) for the mice treated with 0mM, 10 mM, 40 mM and 75 mM meglumine was 771±214.6 days, 834±124 days,927±80.3 days and 1,027±117.5 days. Animals treated with 10 mM, 40 mMand 75 mM lived, respectively, 8.2%, 20.2%, and 33.2% longer than thecontrol animals.

Example 2: Rat Study

Eighteen male Sprague-Dawley rat (ACE) weighing 150-175 g were dividedinto 3 groups (n=6) and fed a normal diet supplemented with 0 mM, 25 mM,or 75 mM meglumine in the drinking water for 32 weeks.

Advanced Glycation End Product in Skin:

At the end of 32 weeks the ratio of advanced glycation end products (AGEproducts) to total protein was determined in the skin using the ratio offluorescence measurements. A 3 cm² biopsy was taken from the shaveddorsal surface of the rats. The dermis was separated from the epidermisvia immersion in water at 55° C. for 30 seconds, followed by gentlescraping of epidermis. The dermis was placed onto a wire screen cut tofit diagonally into fluorescence spectrometer. Fluorescence was recordedon PE 650-40 fluorescence spectrometer using front surface (“diagonal”)geometry. Fluorescence intensities were monitored at excitation/emissionwavelengths of 270/300 nm, 270/330 nm, 270/360 nm, 270/400 nm, 325/400nm, 270/450 nm and 370/450 nm. For direct comparison at the sameexcitation wavelength, ratios of I(270/330 nm) to I(270/450 nm) wererecorded. These ratios were corrected for different instrumentalresponses at 330 and 450 nm.

The amount of skin AGE products in each of the three cohort groups at 32weeks is illustrated below in Table 1 and FIG. 3; the larger the ratio,the more AGEs were present in the skin. The amount of AGE product in theskin observed in untreated rats decreased by 10% with 25 mM meglumineand 60% with 50 mM meglumine (FIG. 3). However, the trends did not reachstatistical significance.

TABLE 1 Statistical analyses of AGE products in skin of megluminetreated rats for 32 weeks. Water 25 mM Meg 50 mM Meg Mean AGE/Total0.594 ± 0.173 0.486 ± 0.187 0.235 ± 0.067 Protein P value 0.686 0.086(treated vs untreated)

Urinary 3DG Levels:

The level of 3DG was measured in the urine of the rats at 32 weeks. 3DGlevels were measured by GC-MS by reacting 0.1 ml of sample, to which 20picomoles of [U-¹³C] labeled 3DG had been added as an internal standard,with 1 ml of 1 mM 2,3-diaminonaphthalene (DAN) for 24 hours at roomtemperature.

Following reaction with DAN, the sample was extracted with four volumesof ethyl acetate and then dried. The residue was dissolved in 50 μl ofN-methyl-N-(trimethylsilyl)trifluoroacetamide and heated at 65° C. for30 min. 2 μl was analyzed by GC-MS. Levels of 3DG were normalized tocreatinine levels measured with reagents from Oxford Biochemicals.

After 32 weeks, 3DG levels were measured in the urine of rats on waterand treated with 50 mM meglumine. 3DG levels were 33% lower in ratstreated with 50 mM meglumine (FIG. 4) and Table 2. This differencereached statistical significance of <0.005.

TABLE 2 Statistical analyses of urinary 3DG levels in meglumine treatedrats for 32 weeks. Water 50 mM Meg 3DG, uM 0.0891 ± 0.007 0.0598 ± 0.004P value 0.005 (treated vs untreated)

Urinary Isoprostane Levels:

Rat urine from 32 weeks was measured for the presence of isoprostane, amarker for oxidative stress using a competitive ELISA (OxfordBiochemicals, Oxford MI). All values were normalized to creatininelevels to control for differences in urine volume. Creatinine wasmeasured using a kit from Oxford Biochemicals.

After 32 weeks, isoprostane levels were measured in the urine of rats onwater and treated with 50 mM meglumine. As illustrated in FIG. 5 andTable 3, isoprostane levels were 22% lower in rats treated with 50 mMmeglumine. However this trend did not reach statistical significance.

TABLE 3 Statistical analyses of urinary isoprostane levels in megluminetreated rats for 32 weeks. Water 50 mM Meg Isoprostane, ng/ml 2.65 ±0.236 2.05 ± 0.283 P value 0.136 (treated vs untreated)

3DG Adduct Levels in Skin

The presence of imidazolone, a 3DG-derived adduct formed from thereaction of 3DG and arginine was measured by fluorescentimmunohistochemistry, using a monoclonal antibody to imidazolone, AG-1(T. Niwa).

A piece of skin from each rat on water and 50 mM meglumine was fixed informalin, and thin sections were treated with AG-1 antibody and then afluorescent second antibody, and each slide was scanned using afluorescence microscope. The total florescence due to imidazolone overeach slide was measured.

The average fluorescence for skins of rats treated with water or 50 mMmeglumine Rats on meglumine had 25% less imidazolone in their skin (FIG.6) and Table 4, although the difference was not statisticallysignificant.

TABLE 4 Statistical analysis of 3DG adducts levels in skin of megluminetreated rats for 32 weeks. Water 50 mM Meg Fluorescence 790567 ± 83833593320 ± 87404 P value 0.134 (treated vs untreated)

3DG Adduct Levels in Kidney Tubules and Glomeruli:

The 3DG adduct imidazolone was measured in kidney tubules and glomeruliby fluorescent immunohistochemistry using a monoclonal antibody toimidazolone, AG-1 (T. Niwa). Kidneys from each rat on water or 50 mMmeglumine were placed in formalin, and thin sections were prepared. Eachslide was treated with AG-1 and then a fluorescent second antibody, andthen scanned using a fluorescence microscope. The total florescence dueto imidazolone over each structure measured.

The average fluorescence for tubules and glomeruli of rats treated for32 weeks with water or 50 mM meglumine is illustrated in FIG. 7 andTable 5. Rats on meglumine had 13% less imidazolone in their tubules,although the difference was not statistically significant. Similarly,rats on meglumine had 24% less imidazolone in their glomeruli althoughagain the difference was not statistically significant.

TABLE 5 Statistical analysis of 3DG adducts levels in tubules andglomeruli of meglumine treated rats for 32 weeks. Water 50 mM MegFluorescence in 47,081,228 ± 6,407,142  40,158,431 ± 3,644,819 Tubules Pvalue Tubules 0.369 Fluorescence in 85,039,251 ± 13,401,970 64,376,501 ±7,548,981 Glomeruli P value Glomeruli 0.2 

Example 3 Glucose Tolerance Test

Mutant KK.Cg-A^(y/+)/J “yellow mice” (which are prone to developingdiabetes and obesity) and control KK.Cg-A^(+/+)/J “black mice” were fedwith water or water supplemented with 18 mM meglumine hydrochloride for16 weeks. As a comparison group, SV129 normoglycemic mice were fed withwater. The animals were then fasted overnight and blood glucose measured(time 0 min). The animals were injected with glucose, and blood glucoselevels measured after 15 min, 30 min, 60 min and 120 min. The resultsare illustrated in FIG. 8.

The mutant yellow mice that were treated with meglumine showed decreasedblood glucose levels at 15 min, 30 min, 60 min and 120 minutes ascompared to those treated with water.

Triglyceride Levels

Serum triglyceride levels were measured in KK.Cg-A^(y/+)/J diabetic micetreated with 18 mM meglumine hydrochloride in the drinking water for 32weeks. The control animals (n=10) had an average of 752.21±2 01.29 mg/dLand the meglumine treated animals (n=9) had an average of 322.66±158.85mg/dL. A t-test was used to compare the mean values and a p<0.001 wascalculated, indicating the decrease in plasma triglycerides in themeglumine treated mice is statistically significant.

Urinary Albumin/Creatinine

Urinary creatinine and albumin levels were measured in KK.Cg-A^(y/+)/J“mutant” diabetic mice and KK.Cg-A^(+/+)/J “control” mice treated withor without 18 mM meglumine hydrochloride in the drinking water for 12weeks. The control mice had an albumin/creatinine ratio of 2.5±1.2(n=6), and the control mice treated with meglumine had a ratio of1.6±1.8 (n=6). The mutant mice had a ratio of 17.3±15.4 (n=6) and themutant mice treated with meglumine had a ratio of 12.4±8.7 (n=6). Forboth control and mutant animals, meglumine treatment resulted in adecreased ratio, and a t-test comparison of the mean values did notindicate the difference was significant.

Example 4: Strength Testing in Mice

A group of SV129 mice (n=15) and a group of mice treated with 18 mMmeglumine hydrochloride in their drinking water (n=15) for 6 weeks weretested for the ability to hold on to an inverted metal grid. The lengthof time before falling off the grid was averaged, and the standard errorwas calculated.

The length of time that the animals could hold on to the grid was6.3±3.4 seconds for the control group and 17.8±0.6 seconds for themeglumine group. A t-test comparison of the mean values was used todetermine a p value=0.0006, indicating the results are significant.

Example 5: Effects of Meglumine in a Human Subject

A 59.5 year-old male suffering from right knee joint pain, and otherwisein good health, was orally administered 500-1,500 mg of megluminehydrochloride on a daily basis over the period of 5 years (with twomonths off).

Over the period of the experiment, the subject experienced an overallweight loss/control effect, with an increase in muscle-to-fat index,strengthening of leg muscles and an increase of 1 inch in arm diameter.The subject further experienced improved muscle strength: he increasedhis military press weights from 200 lb to 355 lb, and was able to docrunches with 100 kgs sets of 25×4.

The subject's skin condition also improved, with the skin feeling smoothand well hydrated, and without development of age spots or wrinkles. Thesubject also experienced improved sexual stamina and sexual performance,with erections lasting for hours.

The subject experienced improved vitality or energy levels, performinghard work functions for up to 9 hours consistently. The subject'sreflexes became quicker, and his olfaction senses were heightened.

The subject experienced increased mental capacity, with improvements inmemory and development of vivid and detailed dreams. The subjectdescribed feeling as mentally active as a teenager.

Example 6: Effects of Meglumine in a Human Subject

A 83 year-old female suffering from high blood pleasure was orallyadministered meglumine hydrochloride on a daily basis over the period ofone month.

Over the period of the experiment, the subject's blood pressure wasreduced from 220/110 to normal range (around 130/78).

The subject experience better sleep and felt more energetic. The subjectalso experienced weight loss, losing at least one dress size.

Example 7: Effects of Meglumine in a Human Subject

A 76 year-old female on a blood thinner medication was orallyadministered meglumine hydrochloride on a daily basis over the period of1 month.

After that period she was able to discontinue the use of the bloodthinner.

Example 8: Effects of Meglumine in a Human Subject

A 46 year-old male was overweight and suffering from fatty liver,experienced sore joints, lacked energy and required extended recoverytime after exercise & travel, was orally administered 500-1,500 mg ofmeglumine hydrochloride on a daily basis over the period of 14 months.

Over the period of the experiment, the subject experienced an overallweight loss/control effect, with a reduction in weight on average from108 kg to 102 kg, at approximately 0.5 kg lost per month. The subjectfurther experienced improved muscle strength and substantial strengthincrease (“about 100 lbs stronger than when I was 25 years old playinghigh level sports”).

The subject's skin condition also improved, with a visually noticeablemarked improvement in entire skin condition both in reduction of sunspots & texture (softening). The subject also experienced improvedsexual stamina and sexual performance.

The subject experienced improved vitality or energy levels, includingoverall reflexes and ability of recovering from travel and exercise.

The subject experienced increased mental capacity, with improvement inmemory, retention of data, concentration levels and problem solving.

The subject also experienced improvement in nail and hair health.

Example 9: Effects of Meglumine in a Human Subject

A 41 year-old female suffering from high blood sugar was orallyadministered meglumine hydrochloride on a daily basis over the period of7 months.

Over the period of the experiment, the subject experienced an overallweight loss/control effect, with loss of 25 pounds without regain of thelost weight. The subject further experienced a decrease in blood glucoselevel from 202 to 75 mg/dL.

The subject experienced improved vitality or energy levels, includingoverall reflexes and ability of recovering from travel and exercise.

The subject's skin condition also improved, with the skin feeling softerand more blemish free.

The subject also experienced dramatically improved sexual stamina andsexual performance.

The subject experienced improved vitality or energy levels, with theability of using heavier weights when working out and recovering fasterfrom exhaustive activities.

The subject experienced increased mental capacity, feeling more focusedand with better reasoning skills.

The subject also experienced improvement in nail and hair health.

Example 10: Effects of Meglumine in a Human Subject

A 69-year-old woman, suffering from scleroderma and type 2 diabetes,overweight and with difficulty to lose through dieting and exercise,experiencing less energy than when younger, was administered megluminehydrochloride (500 mg to 2000 mg) orally almost every day over 5 years.

The subject lost over 30 pounds over the first two and one half yearswithout dieting or increasing exercise activity. The subject was able tomaintain her weight.

The subject's blood glucose level improved upon being administering thecompound (at a minimum dose of 500 mg three times a day). Her insulinand creatine/albumin levels are normal.

The subject's cholesterol levels went from 300 to 265 without dietchange or any medicines. Her LDL level went from 209 to 160 within thelast 16 months; her HDL levels stayed the same. Her CRP level went down(from 0.58 to <0.3), and so did her Lp-PLA level. Her fibrinogenhomocysteine levels stayed the same.

The subject's overall energy levels have increased and the subject'smassage therapist stated that the subject's limbs were more flexible andthe subject was able to stretch more. The subject's appearance isyounger, and her overall skin tone and texture have improved. Thesubject's mental capacity has not deteriorated over the period oftesting. The subject's eye sight has improved over that period.

Example 11: Effects of Meglumine in a Human Subject

A 68-year-old woman, suffering from type 2 diabetes, overweight (heightof 5 feet 1 inch, and weight of 129 pounds, as of month 0) and withdifficulty to lose weight through dieting and exercise, was administeredmeglumine hydrochloride (3×500 mg) orally over the period of 8 months.Over the duration of the study the subject was also administeredmetformin orally to manage her type 2 diabetes.

The subject's blood was analyzed for lipids, lipoprotein particles andapolipoproteins, and inflammation/oxidation markers. The results aresummarized in Table 6.

TABLE 6 Reading Reading Class Subclass month 0 month 8 Lipids (mg/dL)total cholesterol 265 205 LDL-C direct 160 111 HDL-C 69 71 triglycerides135 82 non-HDL-C (calculated) 196 134 Lipoprotein Particles Apo B(mg/dL) 133 79 and Apolipoproteins LDL-P (nmol/L) 2,250 1,529 sdLDL-C(mg/dL) 56 28 % sdLDL-C (calculated) 35 25 Apo A-I (mg/dL) 183 176 HDL-P(μmol-L) 44.3 43.7 HDL2-C (mg/dL) 19 22 Apo B:Apo A-I ratio 0.73 0.45(calculated) Lp(a) mass (mg/dL) 5 6 Inflammation/ Lp-PLA₂ (ng/mL) 152172 Oxidation hs-CRP (mg/L) <0.3 0.3 fibrinogen (mg/dL) 332 334

The disclosures of each and every patent, patent application, andpublication cited herein are hereby incorporated herein by reference intheir entirety.

While this invention has been disclosed with reference to specificembodiments, it is apparent that other embodiments and variations ofthis invention may be devised by others skilled in the art withoutdeparting from the true spirit and scope of the invention. The appendedclaims are intended to be construed to include all such embodiments andequivalent variations.

What is claimed is:
 1. A composition comprising meglumine or a saltthereof and a therapeutic agent selected from the group consisting ofα-glucosidase inhibitors, lipase inhibitors, sulfonyl ureas,meglitinides, biguanides, thiazolidinediones, pramlintide, incretinmimetics, DPP-IV inhibitors, a salt thereof, and any combinationsthereof.
 2. The composition of claim 1, wherein the therapeutic agentcomprises metformin.
 3. The composition of claim 1, further comprising:a first amount of a sweet-tasting compound, wherein the composition issuitable for oral consumption by a subject; wherein the sweetness of thecomposition is equivalent to the sweetness of a second amount of thesweet-tasting compound, further wherein the composition is healthier, isless toxic or has fewer undesirable physiological effects in the subjectthan the second amount of the sweet-tasting compound.
 4. The compositionof claim 3, wherein the sweet-tasting compound comprises glucose,dextrose, high-fructose corn syrup, mannitol, sorbitol, stevia, xylitol,acesulfame potassium, alitame, aspartame, a salt ofaspartame-acesulfame, cyclamate, dulcin, glucin, neohesperidindihydrochalcone, neotame, saccharin, sucralose, or any combinationsthereof.
 5. The composition of claim 3, wherein the subject is a mammal.6. The composition of claim 3, wherein the mammal is a human.
 7. Thecomposition of claim 1, wherein the meglumine salt is formed betweenmeglumine and an acid selected from the group consisting of sulfate,hydrogen sulfate, hydrochloric, hydrobromic, hydriodic, nitric,carbonic, sulfuric, phosphoric, formic, acetic, propionic, succinic,glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic,glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic,anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic,methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic,trifluoromethanesulfonic, 2-hydroxyethane sulfonic, p-toluenesulfonic,sulfanilic, cyclohexylaminosulfonic, stearic, alginic, β-hydroxybutyric,salicylic, galactaric, and galacturonic acid.
 8. A method, comprisingadministering the composition of claim 1 to a subject, wherein thecomposition is administered to the subject by a route selected from thegroup consisting of inhalational, oral, rectal, vaginal, parenteral,topical, transdermal, pulmonary, intranasal, buccal, ophthalmic,intrathecal, parenteral, intravenous, and any combinations thereof. 9.The method of claim 8, wherein the composition is administered to thesubject at a frequency selected from the group consisting of once a day,twice a day, three times a day, four times a day, once a week, twice aweek, three times a week, four times a week, once a month, twice amonth, and any combinations thereof.
 10. The method of claim 8, whereinthe composition is administered to the subject at a dosage ranging fromabout 1 ng/kg/application to about 100 g/kg/application.
 11. The methodof claim 10, wherein the composition is administered to the subject at adosage ranging from about 1 ng/kg/application to about 100mg/kg/application.
 12. The method of claim 8, wherein the composition isadministered to the subject as a controlled-release formulation.
 13. Themethod of claim 8, wherein the subject is a mammal.
 14. The method ofclaim 13, wherein the mammal is a human.
 15. The method of claim 8,wherein the meglumine salt is formed between meglumine and an acidselected from the group consisting of sulfate, hydrogen sulfate,hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric,phosphoric, formic, acetic, propionic, succinic, glycolic, gluconic,lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric,pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic,phenylacetic, mandelic, embonic, methanesulfonic, ethanesulfonic,benzenesulfonic, pantothenic, trifluoromethanesulfonic,2-hydroxyethanesulfonic, p-toluenesulfonic, sulfanilic,cyclohexylaminosulfonic, stearic, alginic, β-hydroxybutyric, salicylic,galactaric, and galacturonic acid.